Project Summary Nausea, vomiting, and anorexia are common side effects of enumerable therapeutic drugs, diseases, and disease treatments. An extreme example of this is emetogenic chemotherapy (EC)-induced nausea and vomiting (CINV) and energy balance dysregulation, which devastate quality of life and obviate treatment adherence. Strikingly, complete control of CINV and energy balance dysregulation has not been achieved, despite the fact that an estimated 650,000 cancer patients undergo chemotherapy each year. The neural circuits that are engaged by chemotherapy to produce CINV and energy balance dysregulation remain elusive. Recent data identify a circuit of EC-activated nucleus tractus solitarius (NTS) neurons that project to the lateral parabrachial nucleus (lPBN), and EC-activated lPBN neurons that project to the central nucleus of the amygdala (CeA) in the rat. Further results indicate that CeA glutamate receptor signaling, potentially via the lPBN?CeA projection, is necessary for the full expression of EC-induced pica (a validated rodent model of nausea/malaise), anorexia, and weight loss. Though these data begin to outline a circuit of CNS sites through which EC-induced malaise and anorexia are mediated, important details of the circuit remain unknown. Specifically, the functional relevance, neurochemical phenotypes, modulatory inputs, and target projections of these hindbrain-forebrain neural populations must be directly investigated to uncover novel targets for the treatment of CINV and energy balance dysregulation. To this end, the innovative approaches in this proposal combine state-of-the-art neuroscience techniques to [1] investigate the functional role of projection- and cell type-specific neuron populations in the mediation of CINV and energy dysregulation, [2] examine the neuropeptide/signaling phenotype(s) and post-synaptic targets of EC-activated CeA neurons, and [3] examine the modulatory role of central GLP-1 signaling in the NTS, lPBN, and CeA in CINV and energy dysregulation. The proposed experiments will use and compare non-vomiting and vomiting laboratory animal models to maximize translational potential of this work. Overall, these studies will expand our understanding of the mechanisms mediating chemotherapy-induced malaise and energy balance dysregulation by revealing the neurocircuitry and chemical signals that produce these undesirable side effects. Additionally, results will identify new target neuron populations and/or neurochemical/peptide systems for the development of novel treatments of CINV and energy balance dysregulation.